Sequence analyses of CYP2B genes and catalytic profiles for P450s in Qdj:Sprague-dawley rats that lack response to the phenobarbital-mediated induction of CYP2B2.
In: The Journal of Pharmacology and Experimental Therapeutics, Jg. 295 (2000-12-01), Heft 3, S. 986-993
serialPeriodical
Zugriff:
The Qdj:Sprague-Dawley (SD) rat is a mutant strain lacking in phenobarbital (PB)-mediated induction of CYP2B2. The presence of interindividual differences in the hepatic content of CYP2B proteins and testosterone 16beta-hydroxylase activity demonstrated that the breeding colony of Qdj:SD rats involves normal (+/+) and intermediate (+/-) phenotypes as well as mutant (-/-)-type rats. Although PB-treated Qdj:SD (-/-) rats expressed CYP2B1 normally, testosterone 16beta-hydroxylase activity in these rats was quite low. Analysis of regioselective metabolism of testosterone and 4-hydroxybiphenyl glucuronidation demonstrated normal catalytic activities associated with other forms of cytochrome P450s, including CYP2A, -2C, and -3A, as well as PB-inducible UDP-glucuronosyltransferase in Qdj:SD (-/-) rats. There were no serious mutations in the exons of the CYP2B1 gene in Qdj:SD (-/-) rats, demonstrating that this gene codes a functional CYP2B1. These observations suggest that CYP2B1 needs the interaction with CYP2B2 to exert the full function. The CYP2B2 gene in Qdj:SD (-/-) rats was the same as that in wild-type (+/+) rats in its length of the region containing all exon/introns and 5'-upstream up to -2.3 kilobase pairs. Malignant mutation such as stop codon formation was not observed in the exons, and no mutation was detected in the region containing the PB-responsive unit. These results strongly suggest that impaired induction of CYP2B2 in Qdj:SD (-/-) rats is attributable either to mutation at the region different from PB-responsive unit and exons or to absence or lowered expression of trans-acting factor(s) necessary for gene regulation.
Titel: |
Sequence analyses of CYP2B genes and catalytic profiles for P450s in Qdj:Sprague-dawley rats that lack response to the phenobarbital-mediated induction of CYP2B2.
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Autor/in / Beteiligte Person: | H, Yamada ; H, Matsunaga ; K, Tsuji ; S, Matsumoto ; M, Yamamoto ; Y, Ishii ; J, Omiecinski C ; K, Oguri |
Zeitschrift: | The Journal of Pharmacology and Experimental Therapeutics, Jg. 295 (2000-12-01), Heft 3, S. 986-993 |
Veröffentlichung: | 2000 |
Medientyp: | serialPeriodical |
ISSN: | 0022-3565 (print) ; 1521-0103 (print) |
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